PROJECT 3: "Vascular Function and Orthostatic Responses in Human Aging"-M..J. Joyner, M.D. The focus of this project is to determine if the sympathetic nerves regulate the venous function in human limbs and contribute to the physiological defense against orthostatic stress. Our rationale is that venous pooling in the lower extremities initiates orthostatic stress. Our data suggests that in normal humans, the sympathetic nerves can evoke venoconstriction and reduce venous pooling, and that venous function is altered with normal aging in a manner which limits pooling and maintains orthostatic tolerance in this population. Additional pilot work suggests that 6these venomotor responses are altered in the Postural Orthostatic Tachycardia Syndrome (POTS), and in patients with autonomic failure. The overall hypothesis is that there can be substantial venoconstriction in normal humans and that this venoconstriction is augmented in healthy older subjects and dysfunctional in patients with POTS and autonomic failure. Our alternative hypothesis is that blunted beta2-mediated peripheral vasodilator responses are responsible for the maintenance of orthostatic tolerance in older subjects and augmented beta2 dilution contributes to the orthostatic intolerance in patients with POTS. To address these hypotheses, the following specific aims will be studied: (1) We will determine if normal aging is associated with altered venous compliance and/or capacitance in the lower extremities Parallel studies will be conducted in patients with POTS and various forms of autonomic failure. (2) We will investigate the role of sympathetic tone and limb blood flow as determinants of lower extremity venous function in healthy older and young subjects and also in the patients. (3) We will determine if beta2- mediated skeletal muscle vasodilation is blunted in the legs of older subjects and augmented in patients with POTS. By studying these issues in healthy older subjects and patients with specific forms of orthostatic intolerance we will learn how the sympathetic nerves regulate lower extremity venous function in humans and how this function is altered with aging and orthostatic intolerance. These studies will permit us to better understand orthostatic intolerance in humans.